Gonadal steroids are major neuroregulators and presumably underlie gender-related differences (sexual dimorphisms) in brain structure and function. We have studied reproductive endocrine-related mood disorders as well as developed endocrine models for these disorders in order to characterize the role of gonadal steroids in affective disturbance. Our major recent findings are as follows: 1) Preliminary evidence of depression induced by medroxyprogesterone but not placebo when added to estrogen in postmenopausal women. 2) Significant increases in cortical excitability (measured by paired pulse transcranial magnetic stimulation) in the late follicular phase compared with the early follicular or luteal phase. 3) Preliminary suggestion of decreased cortical excitability and loss of menstrual cycle modulation of excitability in women with PMS compared with controls. 4) Demonstration that no single set of operational criteria optimizes selection of both symptomatic cycles in women with PMS and asymptomatic cycles in controls. 5) No differences between PMS patients and controls in the genotype or allele frequencies for the following polymorphisms: SLC6A4 promoter VNTR, HTR2C CYS23SER, HTR2A HIS452TYR, and HTR2A T102C. 6) Preliminary evidence of increased frequency of the serotonin receptor 2C CYS 23 SER polymorphism in women with a history of postpartum depression. 7) Progesterone, but not estradiol, increases cortisol (significantly) and ACTH (trend) secretion compared with an induced hypogonadal condition (n = 8). Similar increased cortisol levels are seen following dexamethasone during progesterone replacement. These data may help explain observed menstrual cycle phase-related differences or sexual dimorphisms in the stress response. For example, the ACTH and AVP responses to exercise stimulation in women are increased in the luteal phase. Further, preliminary data show that the ACTH response to exercise stimulation is higher in males than in females, and in contrast to women, men show no difference in stimulated pituitary-adrenal response during hypogonadal compared with eugonadal conditions. 8) Non-depressed postmenopausal women differ in their ability to discriminate estradiol (3/8) or progesterone (2/7) from placebo. These data identify, for the first time, that gonadal steroids are discriminable in some, but not all, human subjects and provide an independent potential model for examining the differential behavioral sensitivity to gonadal steroids seen in women with premenstrual syndrome. 9) Differential susceptibility to gonadal steroid-related depressions in women with a history of premenstrual syndrome or postpartum depression compared with controls. These observations, then, demonstrate not only the marked impact of gonadal steroids on neuroendocrine function and behavior in humans, but demonstrate as well that women with histories of reproductive endocrine-related mood disorders display abnormal responses to normal levels of gonadal steroids. - depression, menstrual cycle, gonadal steroids, postpartum depression, HPA axis - Human Subjects